3-carbamoyloxy derivatives of 5-(tertiaryaminopropylidene) - 5h - dibenzo(a,d)cycloheptenes



United States Patent US. Cl. 260482 7 Claims ABSTRACT OF THE DISCLOSUREThe new tranquilizer compounds disclosed herein in clude carbamoyloxyderivatives of S-(tertiaryaminopropylidene)-H-dibenzo[a,d]cycloheptenes,as well as the corresponding 10,11-dihydro derivatives thereof. Thesecompounds are prepared from 2-(4-methoxyphenethyl) benzoyl chloride byreaction with stannic chloride to produce 3-methoXy-10,11 dihydro SHdibenzo[a,d] cyclohepten-S-one; converting said S-keto compound to3-hydroxy-5 (3 dimethylaminopropylidene) 10,11-dihydro-5Hdizenzo[a,d]cycloheptene by reaction in either order with (1)dimethylaminopropyl magnesium chloride to form the5-hydroXy-5-(3-dimethylaminopropyl) derivative followed by dehydrationto the corresponding 5-(3-dimethylaminopropylidene) derivative and (2)cleavage of the 3-methoxy substituent (with pyridine hydrochloride inthe case of the 10,11-unsaturated compound) to produce the desired3-hydroxy compound and reaction of the 3-hydroxy-l0,ll-dihydro-5-(3-dimethylaminopropylidene) 5H dibenz0[a,d]cycloheptene with methylisocyanate to produce the desired 3-carbamoyloxy derivative.

This invention relates to new chemical compounds and to a novel methodfor preparing them. In particular, this invention relates to newcarbamoyloxy derivatives of dibenzo-cycloheptene compounds having thefollowing general formula:

and nontoxic acid addition salts thereof wherein R is a lower alkylradical and R" and R, which can be similar or dissimilar, are each loweralkyl radicals, either straight or branched chain, having up to 6-carbon atoms and lower alkyl radicals linked together through an atomselected from the group consisting of carbon, nitrogen and oxygen toform a heterocyclic ring having from five to six atoms therein such asl-piperidyl, 1- pyrrolidyl, 4-morpholinyl and l-lower alkyl4-piperazinyl and X is selected from the group consisting of hydrogen,an alkyl group having up to 6 carbon atoms, a perfluoroalkyl grouphaving up to 4 carbon atoms, a phenyl or a substituted phenyl radical, adialkylamino group having up to 4 carbon atoms, an acylamino grouphaving up to 4 carbon atoms, a perfluoroacylamino group having up to 4carbon atoms, an alkylsulfonylamino group having up to 4 carbon atoms,halogen (fluorine, chlorine, bromine or iodine), an alkoxyl group havingup to 4 carbon atoms, a perfiuoroalkoxyl group having up to 4 carbonatoms, cyano, carbamyl, an alkylcarbamyl group having up to 4 carbonatoms, a dialkylcarbamyl group having up to 8 carbon atoms, a carbalkoxygroup having up to 6 carbon atoms, an alkylmercapto group having up to 4carbon atoms, a perfluoroalkylmercapto group having up to 4 carbonatoms, an alkylsulfonyl group having up to 4 carbon atoms, aperfluoroalkylsulfonyl group having up to 4 carbon atoms, sulfamyl, analkylsulfamyl group having up to 4 carbon atoms, or a dialkylsulfamylgroup having up to 8 carbon atoms. Still more particularly it relates tocompounds of the above general formula wherein the carbamoyloxysubstituent is attached at the 3-po-sition. Compounds of this type areincluded in the following general formula:

R1! CHOHzCHzN wherein R, R" and R'" are as indicated above as well asthe acid addition salts thereof.

The compounds of this invention have been found to be valuableparticularly because of their tranquilizing properties. In addition,they are useful because of their antidepressant activity, They are alsouseful as antihistaminic agents. For administration to patientsrequiring either a tranquilizer or an antidepressant drug, the compoundsare preferably administered as the acid addition salt. The particularacid used to prepare the acid addition salt is of little consequenceprovided only that it be nontoxic. The acid addition salts areconsidered to be essentially equivalent in activity to the free basefrom a therapeutic standpoint. The compounds may be administered incapsules, tablets, elixirs, or in other oral or parenteral dosage formsin amounts of from 20 to 1000 mg./day, perferably given in divided dosesthroughout the day. This invention also contemplates the amine oxidesand quaternary salts of the subject compounds.

The process of our invention includes reaction of a compound having thefollowing general formula:

wherein R" and R are as defined above with an alkyl isocyanate to formthe desired 5-(3-dialkylaminopropylidene) 5'H-dibenzo[a,d]cycloheptenehaving an N-alkyl carbarnoyloxy substituent attached to one of thecarbons of the benzenoid ring.

By selection of the appropriate starting material, there are formed asrepresentative compounds of our invention 3- (N-methylcarbamoyloxy)3-dimethylaminopropylidene -5H-dibenzo [a,d cycloheptene;

7-chloro-3- N-ethylcarb amoyloxy -5- 3-dimethylaminopropylidene)-5H-dibenzo [a,d] cycloheptene 7-methyl-3 N-propylcarbamoyloxy -5-3-dimethylaminopropylidene -5 H-dibenzo [a,d] cycloheptene;

3- (N-butylcarbamoyloxy -8-trifiuoromethyl-5- 3-dimethylaminopropylidene) -5H-dibenzo [a,d 1 cycloheptene;

3- (N-isopropylcarbamoyloxy -7-phenyl-5- 3 -dimethylaminopropylidene-5H-dibenzo [a,d] cycloheptene;

7-chloro-3- N-isobutylmethylcarbamoyloxy) -5 3-dimethylaminopropylidene)-5H-dibenzo a,d] cycloheptene;

7-dimethylamino-3- (N-rnethylcarbamoyloxy) -5-3-dipropylaminopropylidene) -5H-dibenzo [a,d] cycloheptene;

3- (N-methylcarbamoyloxy) -8-methylsulfonyl-5-3-dibutylaminopropylidene) -5H-dibenzo [a,d] cycloheptene;

3- (N-methylcarbamoyloxy) -9-methylsulfam0yl-5- (3-diisopropylaminopropylidene -5H-dibenzo [a,d,] cycloheptene;

7-chloro-3-(N-methylcarb amoyloxy)-5-(3-dimethylaminopropylidene) -5H-dibenzo [a,d, cycloheptene;

7-methyl-3-(N-m ethylcarbamoyloxy)-5 -(3 -dimethylaminopropylidene-5H-dibenzo [a,d] cycloheptene 7-ethy1-3- (Nmethylcarbamoyloxy) -5-3-dirnethylaminoproylidene -5H-dibenzo a,d] cycloheptene;

3- (N-methylcarbamoyloxy -7-trifluoromethyl-5-3-dimethylaminopropylidene -5H-dibenzo [a,d] cycloheptene;

3 -(N-methylcarbamoyloxy) -7-phenyl-5- (3 -dimethylaminopropylidene-5H-dibenzo a,d] cycloheptene;

7-dimethylamino-3- (N-methylcarbamoyloxy) -5- (3 -dimethylaminopropylidene -5H-dibenzo [a,d] cycloheptene;

7-methoxy-3 (N-methylcarbamoyloxy -5- 3-dimethylaminopropylidene) -5H-dibenzo a,d] cycloheptene;

7-methylsulfonyl-3- N-methylcarbamoyloxy -5-( 3-dimethylaminopropylidene-5H-dibenzo a,d] cycloheptene;

7-chloro-3 (N-methylcarbamoyloxy) -5- [3 -(1-metl1yl-4- piperazinyl-propylidene] -5H-dibenzo [a,d] cycloheptene;

7-methyl-3 (N-methylcarbamoyloxy) -5- [3 4-rnorpholinyl propylidene]-5H-dibenzo a,d] cycloheptene;

3-(N-methylcarbamoyloxy -7-trifluoromethyl-5- [3 lpiperidyl)propylidene] -SH-dibenzo a,d cycloheptene;

3 N-methylcarbamoyloxy) -7-trifluoromethyl-5- 3 lpyrrolidyl)propylidene] -5H-dibenzo [a,d] cycloheptene.

The corresponding 10,11-dihydro compounds as, for example,5-(3-dimethylaminopropylidene) 3 (N-methylcarbamoyloxy) 10,11dihydro-5H-dibenzo[a,d]cyclo heptene are likewise prepared in similarmanner by selection of the appropriate 10,1l-dihydro compoundcorresponding to the general formula hereinabove as starting material.

The reaction is preferably accomplished by mixing the3-hydroxy-5-(3-dial'kylaminopropylidene) 5H dibenzo [a,d]cycloheptene orthe corresponding 10,11-dihydro derivative with an excess of theselected alkyl isocyanate at ambient temperature. The reaction proceedsreadily and requires no added catalyst or solvent to prepare the desiredcompound in essentially quantitative yield, though a solvent having noactive hydrogen may be used if desired. Thus, after mixing thereactants, the mixture is allowed to stand for up to about 1-5 hours ata temperature of from 0 to 100. Preferably it is carried out at aboutroom temperature (25 C.). The carbamoyloxy product formed in this manneris readily recovered by evaporation of excess reactant or added solventleaving the free base present as a residual amorphous solid. The solidbase is preferably further purified by crystallization of the acidaddition salt. To accomplish this purification it is only necessary todissolve the product initially obtained in a solvent such as a loweralkanol, for example, isopropyl alcohol, methyl alcohol, or ethylalcohol and mix the alcoholic solution with a chemically equivalentamount of the selected acid dissolved in the same solvent to form thedesired salt. The salt is readily precipitated by the addition of etherto the alcohol solution and the crystalline acid addition salt isrecovered by filtration.

In accordance with a further embodiment of our invention, theabove-mentioned 3-hydroXy-5-(3-disubstituted-aminopropylidene)SH-dibenzo[a,dJcycloheptene of the formula is prepared from the known2-(4-alkoxyphenethyl)benzoyl chloride by reaction with stannic chlorideto produce 10,11 dihydro-3-alkoxy-5H-dibenzo[a,d]cycloheptene-5- one,contacting said 3 alkoxydibenzocyclohepten-S-one with an N-bromo amideor an N-bromo imide to produce a monobrominated derivative of10,11-dihydro-3-alkoxy- 5H-dibenzo[a,d]cyclohepten-S-one,dehydrobrominating said monobrominated derivative 'by heating in thepresence of a tertiary amine with consequent production of 3alkoxy-SH-dibenzo[a,d]cyclohepten-5-one and subsequently heating said3-alkoxy compound with pyridine hydrochloride to convert said 3-alkoxysubstituent to a 3- hydroxy substituent and produce3-hydroxy-5H-dibenzo- [a,d]cyclohepten-5-one, condensing said 3-hydroxycompound with a tertiaryaminopropyl Grignard reagent of the formulawherein R" and R' are as previously defined and X is halo, followed byhydrolysis of the Grignard adduct obtained to produce the corresponding3-hydroxy-5-tertiaryarninopropyl-SH-dibenzo[a,d]cyclohepten-S-ol anddehy drating this carbinol by means of an acidic dehydrating agent toproduce the corresponding S-tertiaryaminopropylidene-SH-dibenzo [a,d]cycloheptene.

The corresponding 10,1l-dihydro-3-hydroxy-5-tertiaryaminopropyl 5Hdibenzo[a,d]cyclohepten-S-ol compounds are prepared in accordance withan alternate process of our invention by heating 3-alkoXy-10,1l-dihydro-5H-dibenzo[a,d]cyclohepten-S-one with a hydrohalogen acid selected fromhydrochloric, hydrobromic or hydriodic acid, to produce thecorresponding 3-hydroxy-l0, l1 dihydro-5H-dibenzo[a,d]cyclohepten-5one,condensing said 3 hydroxy-l0,l1-dihydrodibenzocyclohepten-S- onecompound with a Grignard reagent of the formula:

wherein R, R and X are as previously described to produce 3-hydroxy-5-3-tertiaryaminopropyl)-10, l l-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol,dehydrating said intermediate 5-01 compound by heating in the presenceof a strongly acidic reagent to produce the desired 3-hydroxy- 5-(3tertiaryaminopropylidene)-10,l ldihydro-SH-dibenzo [a,dJcycloheptene.The processes of our invention as set forth in the preceding broaddescription are outlined in the flow sheet which follows.

V OR OR II II O OH OH X X i OH OH /RII /RII IIO/\CH2OH:2CH2N\ HOCH2OHzCH2N\ R!!! RI! In the process outlined above a solution of 2-(4-alkoxyphenethyl)benzoic acid in an inert anhydrous nonpolar organicsolvent is mixed with an agent such as thionyl chloride or phosphorustrichloride to produce 2- (4-alkoxyphenethyl)benzoyl chloride. It ispreferred to remove the excess reagent and the solvent by distillationunder reduced pressure. The residue comprising 2-(4-alkoxyphenethyl)benzoyl chloride is then dissolved in an inert solventsuch as an aromatic hydrocarbon as, for example, benzene, toluene,xylene and the like, and mixed with at least an equimolar amount ofstannic chloride. The reactants are stirred together at a temperature offrom 0 to 25 for a period of about 3 hours, following which the reactionmixture is treated with aqueous acid to liberate the product. The3-a1koxy 10,11 dihydro-SH-dibenzo [a,d]cyclohepten-5-one formed isisolated by extraction with a solvent such as methylene chloride andpurified by distillation.

The purified 3-alkoxy-10,1l-dihydro-5H-dibenzo[a,d] cyclohepten-S-one isthen converted to the corresponding 3-hydroxy compound by heating in thepresence of a concentrated hydrohalogen acid such as hydrobromic orhydrochloric acid for a period of several hours. We prefer to usehydrobromic acid since milder reaction conditions may be employed thanwith hydrochloric acid. In the case of hydrobromic acid, heating of thereaction mixture at the reflux temperature for a period of 1 to hours,preferably 4 hours, is sufiicient to accomplish the cleavage of theether substituent in good yield. The reaction medium is preferably aninert, organic liquid as, for example, a lower aliphatic acid such asacetic acid. When the reaction is substantially complete, the product,3- hydroxy-10,11-dihydro 5H dibenzo[a,d]cyclohepten-S- one, is isolatedby dilution of the reaction mixture with Water and extraction of theproduct with a water-immiscible solvent for the product such asmethylene chloride. The product is obtained as a residue afterevaporating the extraction solvent and can be further purified bycrystallization from a suitable solvent.

The purified 3-hydroxy-10,ll-dihydro-SH-dibenzo[a,d] cyclohepten-5-oneis then reacted in solution with a Grignard reagent prepared from a3-dimethylaminopropyl halide and magnesium under anhydrous conditions.Following the reaction, the Grignard adduct obtained is bydrolyzed withwater to produce 3-hydroxy-5-(3-dimethylaminopropyl)10,1l-dihydro-SH-dibenzo[a,d]cyclohepten- 5-01 and the thus-producedcarbinol is then extracted with a suitable solvent and the solvent isevaporated, leaving the product as a residue. The carbinol is furtherpurified, if desired, by recrystallization.

The purified product is then dehydrated using an acidic dehydratingagent. Typical of dehydrating agents which may be employed are strongmineral acids such as hydrochloric acid, trichloroacetic ortrifluoroacetic acid, acetyl chloride, acetic anhydride ortrifluoroacetic anhydride. The reaction is conducted at a temperature offrom 25-l50 C. for a period of from a few minutes to several hours andgives the desired 5- tertiaryaminopropylidene-10,11 dihydro-SH-dibenzo[a,d] cycloheptene which is purified by crystallization as an acidaddition salt. In a typical method of carrying out the dehydration, thecompound 10,1l-dihydro3-hydroxy-5-(3- dimethylaminopropyl -5I-l-dibenzoa,d] cyclohepten 5-01 is heated in solution in trifluoroacetic anhydridewith trifiuoroacetic acid for a period of from 1 to 2 hours at atemperature of about 6080 C.

In preparing the corresponding3-hydroxy-5-(tertiaryaminopropylidene)dibenzo [a,dJcycloheptenecompound, the above-mentioned 3-alkoxy-l0,1l-dihydro-SH-dibenzo[a,d]cyclohepten-5-one is treated in solution with an N- bromo amide orN-bromo imide brominating agent such a N-bromosuccinimide,N-bromophthalide or N-bromoacetamide in the presence of a small amountof an organic per-acid. In carrying out this reaction, the3-alkoxy-10,l1- dihydro-SH-dibenzo[a,d]cyclohepten-5-one is heated withan equimolar amount of the N-bromo imide, whereby mono-bromination ofeither the 10 or ll-position of the dibenzocycloheptenone molecule is:effected. The bromination proceeds rapidly at room temperature and maybe carried out at any temperature between about 15200 C., preferably atabout C. for a period of about 2-4 hours. After removal of the excessreagent, the reaction mixture is washed with aqueous alkali to removeacidic by-products and evaporated under reduced pressure, whereby theproduct is obtained as a crude residue. The recovered product i thenheated in contact with a tertiary amine such as trimethyl amine,triethyl amine, a-picoline, and the like, for a period of from l-20hours. Following the heating with the amine, the desired3-alkoxy-5H-dibenzo[a,d]cyclohepten-S-one is obtained by extraction witha water-immiscible solvent and crystallized.

The crystalline 3-alkoxy-5H-dibenzo[a,dJcyclohepten- 5-one is thenheated with pyridine hydrochloride to effect ether cleavage and producethe corresponding 3-hydroxy compound. It has been found that pyridinehydrochloride is unique in effecting conversion of the 3-alkoxy to the3- hydroxy compound in the SH-dibenzo[a,d1cyclohepten-5- one series.When the ordinary reagents utilized for cleaving ethers to thecorresponding alcohols, such as hydrogen bromide and the like, areemployed, complicating side reactions take place which prevent theisolation of any pure product from the reaction mixture.

In the preferred method, an excess of pyridine hydrochloride and the3-alkoxy-5H-dibenzo[a,d]cyclohepten-S- one are mixed together and heatedto a temperature of from 250 C. for a period of 10 minutes to 2 hours.When 3 methoxy-5H-dibenzo[a,d]cyclohepten-S- one is used as the startingmaterial, the reaction is preferably carried out at about 200 C. forhalf an hour. Following the reaction, the desired 3-hydroxy product isob tained by the addition of water and extraction of the prodnet. Theproduct is then obtained from the extract after removal of the solvent.

The conversion of the thus-obtained3-hydroxy-5H-dibenzo[a,d]cyclohepten-S-one to the desired 3-hydroxy-5-(3-tertiaryaminoalkylpropylidene) H-dibenzo[a,d]cycloheptene is carriedout in the same manner as in the case of the corresponding 10,11-dihydrocompound, that is, by reaction with the appropriate Grignard reagent anddehydration of the carbinol obtained after hydrolysis of the Grignardadduct.

The new compounds of our invention, i.e., the carbamoyloxy derivativesof 5-(tertiaryaminopropylidene)-5H- dibenzocycloheptenes and thecorresponding 10,11-derivatives are usually obtained as a mixture ofgeometric isomers. These isomers which constitute the cis and transisomers are readily separated by fractional crystallization of the basesor the appropriate acid addition salts. The geometric isomers, whenisolated in their pure form, may differ in biological activity.

The following examples are presented to illustrate the methods ofcarrying out the present invention.

EXAMPLE 1 3-(N-methylcarbamoyloxy) -5- (3-dimethylaminopropylidene)-10,1l-dihydro-SH-dibenzo[a,d]cycloheptene (A)3 (p-methoxybenzlidene) phthalide-Phthalic anhydride (89.61 g., 0.605mole), p-methoxyphenylacetic acid (100.52 g., 0.605 mole) and freshlyfused sodium acetate (3.0 g.) are placed in a 500 ml. 3-necked flaskprovided with a thermometer and a condenser set for downwarddistillation. A few boiling chips are added and the flask is heated at255 C. for one hour. Water starts to distill at approximately 220 C.,and a total of 9.2 ml. is collected in a graduated cylinder used as areceiver. After cooling, the crystalline residue is pulverized in amortar, dissolved in four liters of boiling absolute ethanol, filteredwhile hot and the filtrate is concentrated to approximately 2400 ml.After crystallizing overnight at room temperature, the product iscollected and dried at 70 C. Concentration of the mother liquors toapproximately 750 ml. affords additional product melting at 147149 C. Ananalytical sample from another experiment melts at 147.5148 C.

Analysis.Calcd. for C H O percent: C, 76.18; H, 4.80. Found (percent):C, 75.78; H, 5.00.

(B) 2 (p-methoxyphenethyl)benzoic acid.3-(p-methoxybenzylidene)phthalide(52.5 g., 0.21 mole) is dissolved in 1500 ml. of ethanol, sixtablespoonsful of Raney nickel catalyst are added, and the mixture ishydrogenated at 25 and 40 p.s.i. After separating the catalyst byfiltration, the filtrate containing the product is evaporated underreduced pressure to produce the product as a residual solid. The residueis heated on a steam bath for one hour with 400 ml. of saturated sodiumbicarbonate solution, then diluted with 100 m1. of water and washed withthree 200 ml. portions of methylene chloride. The aqueous solution isheated on a steam bath for 45 minutes to completely remove methylenechloride and the turbide solution is filtered through a mat ofSuper-Cel. The clear filtrate is acidified with 3 N hydrochloric acidand the precipitated white solid product collected and washed withwater. After drying at 65 the product melts at 1l6.5118.5.Recrystallization from 100 ml. benzene and 25 ml. hexane yields productmelting at 1181l9.5. An analytical sample from another experiment meltsat 119-120.5.

Analysis.Calcd. forC H O (percent): C, 74.98; H, 6.29. Found (percent):C, 74.63; H, 6.03.

(C) 3-methoxy-10,l1 dihydro-SH-dibenzo[a,d]cyclohepten-5-one.--Asolution of dry ether, 48 ml., containing four drops of dry pyridine iscooled in an ice bath while thionyl chloride, 16 ml., and then2-(p-methoxyphenethyl)-benzoic acid (28.9 g., 0.113 mole) are added.

The mixture is stirred at room temperature for thirty minutes, and thenrefluxed on a steam bath for an additional fifteen minutes. The clearyellow solution is evaporated in a water bath below 40 under reducedpressure and the oily residue consisting of Z-(p-methoxyphenethyl)benzylchloride is dissolved in 16 ml. of dry benzene. The solution is cooledin an ice bath and stirred while a solution of stannic chloride (30 ml.,0.26 mole) in 30 ml. of dry benzene is added over fifteen minutes. Thebrown reaction mixture is stirred in an ice bath for three hours, andthen hydrolyzed with 96 ml. of concentrated hydrochloric acid. Twoadditional identical runs are made. The supernatent solutions from thethree runs are decanted and combined. The black oily residues are mixedwith methylene chloride (600 ml.) and water (225 ml.) and refluxed on asteam bath with stirring for approximately forty-five minutes. Themethylene chloride layer is separated and the extraction is repeatedwith two additional 600 ml. portions of methylene chloride. The combinedmethylene chloride solutions then are used to extract the aqueoussolutions which originally were decanted from the black oily residues.The organic extracts then are washed three times each with 3 Nhydrochloride acid, water, saturated sodium bicarbonate solution andwater. After drying over anhydrous magnesium sulfate, the solvent isremoved under reduced pressure on a steam bath. The brown oily residueis distilled and the product boils as a yellow oil at 150l55 C./0.080.1mm.

(D) 3 hydroxy-10,1l-dihydro-SH-dibenzo[a,d]cyclohepten-5-one.3-methoxy10,11 dihydro-SH-dibenzo- [a,d]cyclohepten-5-one (12.00 g., 0.050 mole)is dissolved in ml. of glacial acetic acid, redistilled 48% hydrobromicacid, 20 ml., is added and the solution is refluxed for four hours undera stream of nitrogen. The reaction mixture is poured into 200 ml. ofwater and extracted three times with ml. portions of methylene chloride.The combined extracts are washed twice with water, then extracted with100 ml. and two 50 ml. portions of 5% sodium hydroxide solution. Thebasic extract is acidified with 6 N hydrochloric acid and extractedthree times with methylene chloride. After washing the extracts withwater and drying over anhydrous magnesium sulfate, the solvent isevaporated on a steam bath under reduced pressure. The solid residue isdissolved in 50 ml. of boiling absolute ethanol, treated withdecolorizing charcoal for forty-five minutes and filtered. The filtrateis concentrated to approximately 30 ml., diluted to incipient turbiditywith water (25 ml.) and the product crystallizes as a tan solid onstanding at room temperature, M.P. 147.5148.3. An analytical sample fromanother experiment melts at 147.5 148.5

Alzalysis.Calcd. for C I-1 0 (percent): C, 80.33; H, 5.40. Found(percent): C, 80.57; H, 5.41.

(E) 3-hydroxy 10,11 dihydro-5-(3-dimethylaminopropyl) 5Hdibenzo[a,d]cyclohepten-5-ol.Magnesium turnings (4.09 g., 0.168 g. atom)are placed in a 300,

ml. 3-necked flask that is equipped with a Hershberg stirrer, refluxcondenser and dropping funnel. An atmosphere of nitrogen is maintainedthroughout the reaction. The magnesium is covered with 20 ml. of dry,peroxide-free tetrahydrofuran and a crystal of iodine is added, followedby ethyl bromide (0.46 g., 0.0042 mole) and fifteen drops of a solutionof 20.44 g., (0.168 mole) of 3-dimethylaminopropyl chloride in 68 ml. oftetrahydrofuran. The mixture is stirred and heated to refluxing untilthe reaction is initiated (approximately five minutes). Heat then isremoved and the remainder of the 3-dimethylaminopropyl chloride solutionis added dropwise at such a rate that gentle refluxing is maintained.When the addition is complete (30 minutes), stirring is continued andthe mixture heated to refluxing for one hour on the steam bath. Thesolution is cooled in an ice-bath and stirred while a solution of3-hydroxy-10,1l-dihydro-SH- dibenzo[a,d]cyclohepten-S-one (9.44 g.,0.042 mole) in 28 ml. of tetrahydrofuran is added over fifteen minutes.

The red solution is stirred in the ice-bath for thirty minutes and thenat room temperature for one hour. The bulk of the solvent is evaporatedunder reduced pressure below 35. The residue is dissolved in 285 ml. ofbenzene and the Grignard adduct hydrolyzed by the dropwise addition of64 ml. of water while cooling in an ice-bath. The benzene layer isdecanted from the gelatinous precipitate which then is extracted withthree 100 ml. portions of boiling benzene. The combined benzene extractsare washed twice with water, then extracted three times with '85 ml.portions of 0.5 M citric acid solution. After washing the benzene layerwith water, the combined washings and acid extracts are carefullyrendered alkaline, first by the addition of 25 ml. of 10 N sodiumhydroxide solution and, finally, with 55 ml. of saturated sodiumbicarbonate solution. The mixture is extracted with three 200 ml.portions of benzene, the combined extracts are washed with water anddried over anhydrous magnesium sulfate. The solvent is evaporated on thesteam bath under reduced pressure and the solid residue is crystallizedfrom 50 ml. of 95% ethanol-29 ml. of water. The product melts at 172173.An analytical sample from another experiment melts at 171.5 -172.5

Analysis.-Calcd. for C H NO (percent): C, 77.13; H, 8.09; N, 4.50. Found(percent): C, 77.50; H, 8.09; N, 4.72.

(F) 3-hydroxy-5-(3-dimethylaminopropylidene)-10,11-dihydro-SH-dibenzo[a,d]cycloheptene.-3 hjydroxy-5-(3-dimet'hylaminopropyl) 10,11 dihydro-SH-dibenzo- [a,d]cyclohepten-5-ol(300 mg., 0.963 millimole) is dissolved in 3 ml. of trifluoroaceticacid, 1.5 ml. of trifluoroacetic anhydride is added and the solution isrefluxed for one hour in a water-bath at 6570. The solvent then isevaporated on the steam bath under reduced pressure, the oily residue issuspended in 25 ml. of saturated sodium bicarbonate solution andextracted three times with methylene chloride. The combined extracts arewashed three times with water, dried over anhydrous magnesium sulfateand the solvent distilled in a water bath under reduced pressure untilthe residue attains constant weight and is recovered as an amorphoussolid product.

(G) 3-(N methylcarbamoyloxy)-5-(3-dimethylaminopropylidene) 10,11dihydro-SH-dibenzo[a,d]cycloheptene-hydrogen oxalate (ct-H3isomers).-3-hydroxy-5- (3-dimethylaminopropylidene) 10,11dihydro-SH-dibenzo[a,d]cycloheptene (n+5 isomers) (264 mg., 0.900millimole) is dissolved in 9 ml. of redistilled methyl isocyanate andthe solution is stirred at room temperature for 20 hours. The solvent isevaporated in a water-bath below 40 under reduced pressure and the oilresidue weighs 316 mg. (100%). A portion of the residue (293 mg., 0.836millimole) is disolved in 5 ml. of isopropyl alcohol, a solution of 83mg. (0.92 millimole) of oxalic acid in 5 ml. of isopropyl alcohol isadded, the solution is concentrated to approximately 7 ml. and ether,1.5 ml., is added to incipient turbidity. On standing at roomtemperature, the product crystallizes as a White solid melting withdecomposition at 170.5. An analytical sample melts at 167.2 withdecomposition and shows a 46.4% slope on solubility analysis.

Analysis.Calcd. for C H N O -C H O (percent): C, 65.44; H, 6.41; N,6.36. Found (percent: C, 65.08; H, 6.21 N, 6.42.

EXAMPLE 2 3 (N-methylcarbamoyloxy) -5- 3 -dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene (A) 3methoxy-5H-dibenzo[a,d]cyclohepten-5-one.- 3-methoxy-10,11-dihydro 5Hdibenzo[a,d]cyclohepten- 5-one prepared as shown in Example 1(C) (19.43g., 0.0815 mole) is dissolved in 167 m1. of carbon tetrachloride,N-bromosuccinimide (72.98 g., 0.41 mole) and then benzoyl peroxide, 295mg., are added and the mixture is stirred and heated to refluxingcautiously. After approximately 15 minutes the reaction is initiated.The mixture is stirred at reflux for two hours, then cooled to roomtemperature and the succinimide separated by filtration. The combinedfiltrate and washings are extracted three times with 5% sodiumhydroxide, washed with water and dried over magnesium sulfate. Thesolvent is distilled on the steam bath under reduced pressure, andtriethylamine, 148 ml., is added to the yellow solid residue. Themixture is heated to refluxing with stirring for 16 hours. Aftercooling, the mixture is diluted with 200 ml. of benzene and washed threetimes with water. After filtering to remove some amorphous material, thebenzene and triethylamine are distilled on the steam bath under reducedpressure. The residue is dissolved in 175 ml. of benzene and thesolution is extracted with 3 N hydrochloric acid, washed with water andthe solvent is evaporated under reduced pressure on the steam bath. Theresidue is sublimed at 0.07 mm. The sublimate is crystallized from 35ml. of cyclohexane and melts at 62-65. An analytical sample from anotherexperiment melts at 68.269.6.

Analysis.-Calcd. for C H O (percent): C, 81.33; H, 5.12. Found(percent): C, 81.68; H, 5.26.

(B) 3 hydroxy-SH-dibenzo [a,d]cyclohepten-5-one.- Pyridine hydrochloride(57.78 g., 0.50 mole) is placed in a 200 ml. 3-necked flask equippedwith a nitrogen inlet tube and drying tube. Under a slow stream ofnitrogen, the flask is heated to 205 when 3-methoxy-5H-dibenzo-[a,d]cyclohepten-5-one (11.64 g., 0.049 mole) is added. The melt isheated at 207 for 30 minutes. After cooling to room temperature, thereaction mixture is distributed between 250 ml. of ethyl acetate and 200ml. of water. The aqueous layer is separated and extracted with two ml.portions of ethyl acetate. The combined ethyl acetate extracts arewashed with water and the solvent is evaporated on the steam bath underreduced pressure. The solid residue is treated with 300 ml. of 1.5%sodium hydroxide solution and extracted with three 100 ml. portions ofbenzene. The alkaline solution is acidified with 3 N hydrochloric acidand extracted three times with 150 m1. of ethyl acetate. After washingwith water, the solvent is evaporated on the steam bath under reducedpressure. The residue is dissolved in 1500 ml. of boiling benzene,filtered while hot and the filtrate concentrated to approximately 400ml. On standing at room temperature, the product crystallizes as ayellow solid melting at 206.5-207.5. An analytical sample from anotherexperiment melted at 206.6-207.9.

Analysis.-Calcd. for C H O (percent): C, 81.06; H, 4.54. Found(percent): C, 80.78; H, 4.58.

(C) 3-hydroxy-5-(3-dimethylaminopropyl)-5H-dibenzo-[a,d]cyclohepten-S-oL-Magnesium turnings (5.11 g., 0.21 g. atom) areplaced in a 500 ml. B-necked flask that is equipped with a Hershbergstirrer, reflux condenser and dropping funnel. An atmosphere of nitrogenis maintained throughout the reaction. The magnesium is covered with 23ml. of dry, peroxide-free tetrahydrofuran and a crystal of iodine isadded, followed by ethyl bromide (580 mg., 0.0053 mole) and 20 drops ofa solution of 25.55 g. (0.21 mole) of 3-dimethylaminopropyl chloride in82 ml. of tetrahydrofuran. The mixture is stirred and heated torefluxing on the steam bath until the reaction is initiated(approximately five minutes). Heat is removed and the remainder of theS-dimethylaminopropyl chloride solution is added dropwise at such a ratethat gentle refluxing is maintained. When the addition is complete (30minutes), stirring is continued and the mixture heated to refluxing forone hour. The solution is cooled in an ice-bath and stirred while asolution of 3-hydroxy-5H-dibenzo [a,d]cyclohepten-5-one (11.66 g.,0.0525 mole) in 70 ml. of tetrahydrofuran is added over 15 minutes. Thered solution is stirred in an ice-bath for 30 minutes and then at roomtemperature for one hour.

The bulk of the solvent is evaporated under reduced pressure below 35.The residue is dissolved in 350 ml. of benzene and the Grignard adducthydrolyzed by the dropwise addition of 82 ml. of water while cooling inan icebath. The benzene layer is decanted from the gelatinousprecipitate which then is extracted with three 100 ml. portions ofboiling benzene. The combined benzene extracts are washed twice withwater, then extracted with 110 ml. and two 80 ml. portions of 0.5 Mcitric acid solution. After washing the benzene layer with water, thecombined washings and acid extracts are carefully rendered alkaline,first by the addition of 80 ml. of N sodium hydroxide solution, followedby 50 ml. of saturated sodium bicarbonate solution. The mixture isextracted with three 250 ml. portions of benzene followed by three 200ml. portions of ethyl acetate. The combined extracts are washed withwater and the solvent is evaporated on the steam bath under reducedpressure. The solid residue is crystallized from 35 ml. of 95%ethanol-2.5 ml. of water. The product melts at 200201 C. An analyticalsample from another experiment melts identically.

Analysis.Calcd. for C H NO (percent): C, 77.64; H, 7.49; N, 4.53. Found(percent): C, 77.47; H, 7.41; N, 4.44.

(D) 3 hydroxy 5 (3-dimethylaminopropylidene)- 5Hdibenzo[a,d]cycloheptene.3 hydroxy 5 (3- dimethylaminopropyl) 5Hdibenzo[a,d]cyclohepten-5 01 (4.00 g., 0.013 mole) is dissolved in 40ml. of trifluoroacetic acid, 20 ml. of trifluoroacetic anhydride isadded and the solution is refluxed for one hour in a water-bath at 6570. The solvent is evaporated on the steam bath under reduced pressure,the residue suspended in 100 ml. of saturated sodium bicarbonatesolution and extracted three times with 60 ml. portions of methylenechloride. The combined extracts are washed three times with water, driedover anhydrous magnesium sulfate and the solvent distilled on the steambath under reduced pressure until the solid product attains constantweight.

(E) 3 (N methylcarbamoyloxy) 5 (3-dimethylaminopropyldiene) 5Hdibenzo[a,d]cycloheptene-hydrogen oxalate (u-l-fi isomers).3hydroxy-S-(3-dimethylaminopropylidene) 5H dibenzo[a,d]cycloheptene(oz-Hi isomers) (968 mg, 0.00332 mole) is dissolved in 33 ml. ofredistilled methyl isocyanate and the solution is stirred at roomtemperature for 2.5 hours. The solvent is evaporated in a water bathbelow 40 under reduced pressure and the amorphous solid residue weighs1.118 g. (97%). A portion of the residue (1.007 g., 0.00289 mole) isdissolved in 4 ml. of absolute ethanol, a solution of 286 mg. (0.00318mole) of oxalic acid in 4 ml. of absolute ethanol is added and ether, 9ml., is added to incipient turbidity. On standing at room temperature,the product crystallizes as a white solid melting at 156 withdecomposition. Concentration of the mother liquors to approximately 2ml., followed by the addition of 12 ml. of ether to incipient cloudinessalfords additional product melting at 157 with decomposition. On mixing,the two crops of product melt with decomposition at 155.5.

Analysis.-Calcd. for C H N O -C H O (percent): C, 65.74; H, 5.98; N,6.39. Found (percent): C, 65.64; H, 6.11; N, 6.44.

In the preceding examples the designations 0c and [3 are used todesignate the individual geometric isomers without regard to theirconfiguration.

What is claimed is:

12 1. The compound having the formula N V o CNHR RI! I CHCHzOHzN and thenon-toxic acid addition salts and N-oxides thereof wherein R is a loweralkyl radical, R" and R' are each lower alkyl radicals or when takentogether with the nitrogen atom are either l-pyrrolidyl, l-piperidyl,4-morpholinyl, or 1-loweralkyl-4 piperazinyl.

2. A compound in accordance with claim 1 having the and a nontoxicaddition acid salt and N-oxides thereof wherein R, R and R' are eachlower alkyl radicals.

6. A compound in accordance with claim 5 wherein R is defined as amethyl substituent.

7. A compound in accordance with claim 5 wherein R" and R' are definedas methyl substituents.

References Cited UNITED STATES PATENTS 2,716,659 8/1955 Kreysa et a1.260471 3,409,640 11/1968 Villani 260-370.8

OTHER REFERENCES Bonvicino et al.: J. Org. Chem., 26, 2383-92 (1961).

Cope et al.: J. Am. Chem. Soc., 73, 1673-8 (1951). Cram et al.: OrganicChemistry, 2nd ed., McGraw- Hill Book Co., New York, N.Y. (1964), pp.217-8.

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner U.S. Cl.X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N 3,547,980Dated December 15, 1970 In Edward L. Engelhardt and Mark B. Freedman Itis certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 3 line 61, insert after "material" in which t1 dotted linerepresents an optional additional bond Colur 4 line 26, delete"cycloheptene" and insert cyclohepten Column 5 line 30, righthandformula, delete the lower R" and insert R'" Column 7 line 60, delete"turbide" and insert turbid Column 8 line 5, delete "l6" and inser1 116line 23, delete "hydrochloride" and insert hyd: chloric Column 12 line14, insert after "piperazinyl" in which the dotted line represents anoptional additional b Signed and sealed this 29th day of June 1971(SEAL) Attest:

EDWARD M.FLETCI-IER,JR. WILLIAM E. SCHUYLERJR Attesting OfficerCommissioner of Patent

